Halichondrins have been disclosed as having anti-cancer and antimitotic activity (Chem. Rev. 2009, 109, 3044-3079, incorporated herein by reference). In particular, Halichondrin B has been reported as a potent anticancer agent that was first isolated from the marine sponge Halichondria okadai (U.S. Pat. No. 5,436,238; Tetrahedron Lett. 1994, 35, 9435 and WO 1993/017690 A1, all incorporated herein by reference). It was further reported that analogs of Halichondrin B bearing only macrocyclic fragment of its molecule (C1-C30 fragment) and having a ketone function instead of ester at C1 position demonstrate anticancer activity similar to Halichondrin B (Bioorg. Med. Chem. Lett., 2000, 10, 1029 and Bioorg. Med. Chem. Lett., 2004, 14, 5551) It was established that such macrocyclic fragment is responsible for induction of mitotic blocks in cancer cells via disruption of tubulin polymerization process that triggers apoptosis of cancerous cells and stops their proliferation (Cancer Res., 2004, 64, 5760 and Mol. Canc. Ther., 2008, 7, 2003). Eribulin mesylate, a macrocyclic C1-keto analog of Halichondrin B, has been reported as having potent anticancer properties (WO 1999/065894 A1, incorporated herein by reference). Eribulin is marketed under the trade name Halaven, and it is also known as E7389, B 1939 and ER-086526.

The synthetic approach described (U.S. Pat. No. 6,214,865; WO 2009/124237 A1, Bioorg. Med. Chem. Lett., 2004, 14, 5551 and J. Am. Chem. Soc. 2009, 131, 15642, all incorporated herein by reference) involves introduction of nitrogen in the C27-C35 fragment of Eribulin after assembly of the macrocycle. Such an approach can add synthetic steps to the later stages of the synthesis, after the building blocks corresponding to the C1-C13 and C14-C26 fragments have been introduced. The synthesis of those fragments is long and complex; and every additional step in the synthesis can imply an increase in manufacturing costs. In addition, due to the cytotoxic nature of Eribulin, late introduction of the nitrogen results in a greater number of steps that can require special safety containment, which can limit throughput and can also increase the cost of producing the active pharmaceutical ingredient (API).
There is a need in the art for a compound that can be used in process for preparation of Eribulin and other macrocyclic C1-keto analogs of Halichondrin B and their salts. In addition, there is a need in the art for a compound and a process that can help to improve the convergence of the synthetic route for preparation of Eribulin and other macrocyclic C1-keto analogs of Halichondrin B and their salts, and therefore, can also help to reduce the amount of C1-C13 and C14-C26 fragments required. Further, there is a need in the art for a compound that can help to reduce the number of steps that can require safety containment for preparation of Halichondrin and its analogs. Moreover, there is a need in the art for a process for preparation of such a compound.